This invention is directed to certain novel macroheterocyclic compounds, methods for producing such compounds and methods for treating or ameliorating a kinase or dual-kinase mediated disorder. More particularly, this invention is directed to macroheterocyclic 1H-indole, 1H-pyrrolo[2,3-b]pyridine, 1H-pyrazolo[3,4-b]pyridine, and 1H-indazole compounds useful as selective kinase or dual-kinase inhibitors, methods for producing such compounds and methods for treating or ameliorating a kinase or dual-kinase mediated disorder.
U.S. Pat. No. 5,624,949 to Heath, Jr., et. al., describes bis-indolemaleimide derivatives of the formula: 
wherein W is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94COxe2x80x94, C2-C6 alkylene, substituted alkylene, C2-C6 alkenylene, -aryl-, -aryl(CH2)mOxe2x80x94, -heterocycle-, -heterocycle-(CH2)mOxe2x80x94, -fused bicyclic-, -fused bicyclic-(CH2)mOxe2x80x94, xe2x80x94NR3xe2x80x94, xe2x80x94NOR3xe2x80x94, xe2x80x94CONHxe2x80x94 or xe2x80x94NHCOxe2x80x94; X and Y are independently C1-C4 alkylene, substituted alkylene, or together, X, Y and W combine to form (CH2)nxe2x80x94AAxe2x80x94; R1 is independently hydrogen, halo, C1-C4 alkyl, hydroxy, C1-C4 alkoxy, haloalkyl, nitro, NR4R5 or xe2x80x94NHCO(C1-C4)alkyl; R2 is hydrogen, CH3COxe2x80x94, NH2 or hydroxy; R3 is hydrogen, (CH2)maryl, C1-C4 alkyl, xe2x80x94COO(C1-C4 alkyl), xe2x80x94CONR4R5, xe2x80x94C(Cxe2x95x90NH)NH2, xe2x80x94SO(C1-C4 alkyl), xe2x80x94SO2(NR4R5) or xe2x80x94SO2(C1-C4 alkyl); R4 and R5 are independently hydrogen, C1-C4 alkyl, phenyl, benzyl, or combine to the nitrogen to which they are bonded to form a saturated or unsaturated 5 or 6 member ring; AA is an amino acid residue; m is independently 0, 1, 2 or 3; and n is independently 2, 3, 4 or 5 as PKC inhibitors and as selective PKCxcex2-I and PKCxcex2-II inhibitors.
It is an object of the present invention to provide macroheterocyclic 1H-indole, 1H-pyrrolo[2,3-b]pyridine, 1H-pyrazolo[3,4-b]pyridine, and 1H-indazole compounds useful as a kinase or dual-kinase inhibitor (i.e., a compound capable of inhibiting two or more kinases such as, for example, a kinase selected from protein kinase C or glycogen synthase kinase-3; and, more particularly, a kinase selected from protein kinase C xcex1, protein kinase C xcex2-II, protein kinase C xcex3 or glycogen synthase kinase-3xcex2), methods for their production and methods for treating or ameliorating a kinase or dual-kinase mediated disorder.
The present invention provides a macroheterocyclic compound of Formula (I): 
wherein
A and E are independently selected from the group consisting of a hydrogen substituted carbon atom and a nitrogen atom; wherein 
is independently selected from the group consisting of 1H-indole, 1H-pyrrolo[2,3-b]pyridine, 1H-pyrazolo[3,4-b]pyridine and 1H-indazole;
Z is selected from O; alternatively, Z is selected from dihydro; wherein each hydrogen atom is attached by a single bond;
R4 and R5 are independently selected from C1-8alkyl, C2-8alkenyl and C2-8alkynyl optionally substituted with oxo;
R2 is selected from the group consisting of xe2x80x94C1-8alkyl-, xe2x80x94C2-8alkenyl-, xe2x80x94C2-8alkynyl-, xe2x80x94Oxe2x80x94(C1-8)alkyl-Oxe2x80x94, xe2x80x94Oxe2x80x94(C2-8)alkenyl-Oxe2x80x94, xe2x80x94Oxe2x80x94(C2-8)alkynyl-Oxe2x80x94, xe2x80x94C(O)xe2x80x94(C1-8)alkyl-C(O)xe2x80x94 (wherein any of the foregoing alkyl, alkenyl and alkynyl linking groups are straight carbon chains optionally substituted with one to four substituents independently selected from the group consisting of C1-8alkyl, C1-8alkoxy, C1-8alkoxy(C1-8)alkyl, carboxyl, carboxyl(C1-8)alkyl, xe2x80x94C(O)Oxe2x80x94(C1-8)alkyl, xe2x80x94C1-8alkyl-C(O)Oxe2x80x94(C1-8)alkyl, amino (substituted with a substituent independently selected from the group consisting of hydrogen and C1-4alkyl), amino(C1-8)alkyl (wherein amino is substituted with a substituent independently selected from the group consisting of hydrogen and C1-4alkyl), halogen, (halo)1-3(C1-8)alkyl, (halo)1-3(C1-8)alkoxy, hydroxy, hydroxy(C1-8)alkyl and oxo; and, wherein any of the foregoing alkyl, alkenyl and alkynyl linking groups are optionally substituted with one to two substituents independently selected from the group consisting of heterocyclyl, aryl, heteroaryl, heterocyclyl(C1-8)alkyl, aryl(C1-8)alkyl, heteroaryl(C1-8)alkyl, spirocycloalkyl and spiroheterocyclyl (wherein any of the foregoing cycloalkyl, heterocyclyl, aryl and heteroaryl substituents are optionally substituted with one to four substituents independently selected from the group consisting of C1-8alkyl, C1-8alkoxy, C1-8alkoxy(C1-8)alkyl, carboxyl, carboxyl(C1-8)alkyl, amino (substituted with a substituent independently selected from the group consisting of hydrogen and C1-4alkyl), amino(C1-8)alkyl (wherein amino is substituted with a substituent independently selected from the group consisting of hydrogen and C1-4alkyl), halogen, (halo)1-3(C1-8)alkyl, (halo)1-3(C1-8)alkoxy, hydroxy and hydroxy(C1-8)alkyl; and, wherein any of the foregoing heterocyclyl substituents are optionally substituted with oxo)), cycloalkyl, heterocyclyl, aryl, heteroaryl (wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one to four substituents independently selected from the group consisting of C1-8alkyl, C1-8alkoxy, C1-8alkoxy(C1-8)alkyl, carboxyl, carboxyl(C1-8)alkyl, amino (substituted with a substituent independently selected from the group consisting of hydrogen and C1-4alkyl), amino(C1-8)alkyl (wherein amino is substituted with a substituent independently selected from the group consisting of hydrogen and C1-4alkyl), halogen, (halo)1-3(C1-8)alkyl, (halo)1-3(C1-8)alkoxy, hydroxy and hydroxy(C1-8)alkyl; and, wherein heterocyclyl is optionally substituted with oxo), xe2x80x94(Oxe2x80x94(CH2)1-6)0-5xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94(CH2)1-6xe2x80x94Oxe2x80x94(CH2)1-6xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94(CH2)1-6xe2x80x94Oxe2x80x94(CH2)1-6xe2x80x94Oxe2x80x94(CH2)1-6xe2x80x94Oxe2x80x94, xe2x80x94(Oxe2x80x94(CH2)1-6)0-5xe2x80x94NR6xe2x80x94, xe2x80x94Oxe2x80x94(CH2)1-6xe2x80x94NR6xe2x80x94(CH2)1-6xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94(CH2)1-6xe2x80x94Oxe2x80x94(CH2)1-6xe2x80x94NR6xe2x80x94, xe2x80x94(Oxe2x80x94(CH2)1-6)0-5xe2x80x94Sxe2x80x94, xe2x80x94Oxe2x80x94(CH2)1-6xe2x80x94Sxe2x80x94(CH2)1-6xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94(CH2)1-6xe2x80x94Oxe2x80x94(CH2)1-6xe2x80x94Sxe2x80x94, xe2x80x94NR6xe2x80x94, xe2x80x94NR6xe2x80x94NR7xe2x80x94, xe2x80x94NR6xe2x80x94(CH2)1-6xe2x80x94NR7xe2x80x94, xe2x80x94NR6xe2x80x94(CH2)1-6xe2x80x94NR7xe2x80x94(CH2)1-6xe2x80x94NR8xe2x80x94, xe2x80x94NR6xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94NR6xe2x80x94, xe2x80x94C(O)xe2x80x94(CH2)0-6xe2x80x94NR6xe2x80x94(CH2)0-6xe2x80x94C(O)xe2x80x94, xe2x80x94NR6xe2x80x94(CH2)0-6xe2x80x94C(O)xe2x80x94(CH2)1-6xe2x80x94C(O)xe2x80x94(CH2)0-6xe2x80x94NR7xe2x80x94, xe2x80x94NR6xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94NR6xe2x80x94, xe2x80x94NR6xe2x80x94C(NR7)xe2x80x94NR8xe2x80x94, xe2x80x94Oxe2x80x94(CH2)1-6xe2x80x94NR6xe2x80x94(CH2)1-6xe2x80x94Sxe2x80x94, xe2x80x94Sxe2x80x94(CH2)1-6xe2x80x94NR6xe2x80x94(CH2)1-6xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94(CH2)1-6xe2x80x94NR6xe2x80x94(CH2)1-6xe2x80x94Sxe2x80x94, xe2x80x94NR6xe2x80x94(CH2)1-6xe2x80x94Sxe2x80x94(CH2)1-6xe2x80x94NR7xe2x80x94 and xe2x80x94SO2xe2x80x94 (wherein R6, R7 and R8 are independently selected from the group consisting of hydrogen, C1-8alkyl, C1-8alkoxy(C1-8)alkyl, carboxyl(C1-8)alkyl, amino(C1-8)alkyl (wherein amino is substituted with a substituent independently selected from the group consisting of hydrogen and C1-4alkyl), hydroxy(C1-8)alkyl, heterocyclyl(C1-8)alkyl, aryl(C1-8)alkyl and heteroaryl(C1-8)alkyl (wherein the foregoing heterocyclyl, aryl and heteroaryl substituents are optionally substituted with one to four substituents independently selected from the group consisting of C1-8alkyl, C1-8alkoxy, C1-8alkoxy(C1-8)alkyl, carboxyl, carboxyl(C1-8)alkyl, amino (substituted with a substituent independently selected from the group consisting of hydrogen and C1-4alkyl), amino(C1-8)alkyl (wherein amino is substituted with a substituent independently selected from the group consisting of hydrogen and C1-4alkyl), halogen, (halo)1-3(C1-8)alkyl, (halo)1-3(C1-8)alkoxy, hydroxy and hydroxy(C1-8)alkyl; and, wherein heterocyclyl is optionally substituted with oxo));
with the proviso that, if A and E are selected from a hydrogen substituted carbon atom, then R2 is selected from the group consisting of xe2x80x94C2-8alkynyl-, xe2x80x94Oxe2x80x94(C1-8)alkyl-Oxe2x80x94, xe2x80x94Oxe2x80x94(C2-8)alkenyl-Oxe2x80x94, xe2x80x94Oxe2x80x94(C2-8)alkynyl-Oxe2x80x94, xe2x80x94C(O)xe2x80x94(C1-8)alkyl-C(O)xe2x80x94 (wherein any of the foregoing alkyl, alkenyl and alkynyl linking groups are straight carbon chains optionally substituted with one to four substituents independently selected from the group consisting of C1-8alkyl, C1-8alkoxy, C1-8alkoxy(C1-8)alkyl, carboxyl, carboxyl(C1-8)alkyl, xe2x80x94C(O)Oxe2x80x94(C1-8)alkyl, xe2x80x94C1-8alkyl-C(O)Oxe2x80x94(C1-8)alkyl, amino (substituted with a substituent independently selected from the group consisting of hydrogen and C1-4alkyl), amino(C1-8)alkyl (wherein amino is substituted with a substituent independently selected from the group consisting of hydrogen and C1-4alkyl), halogen, (halo)1-3(C1-8)alkyl, (halo)1-3(C1-8)alkoxy, hydroxy, hydroxy(C1-8)alkyl and oxo; and, wherein any of the foregoing alkyl, alkenyl and alkynyl linking groups are optionally substituted with one to two substituents independently selected from the group consisting of heterocyclyl, aryl, heteroaryl, heterocyclyl(C1-8)alkyl, aryl(C1-8)alkyl, heteroaryl(C1-8)alkyl, spirocycloalkyl and spiroheterocyclyl (wherein any of the foregoing cycloalkyl, heterocyclyl, aryl and heteroaryl substituents are optionally substituted with one to four substituents independently selected from the group consisting of C1-8alkyl, C1-8alkoxy, C1-8alkoxy(C1-8)alkyl, carboxyl, carboxyl(C1-8)alkyl, amino (substituted with a substituent independently selected from the group consisting of hydrogen and C1-4alkyl), amino(C1-8)alkyl (wherein amino is substituted with a substituent independently selected from the group consisting of hydrogen and C1-4alkyl), halogen, (halo)1-3(C1-8)alkyl, (halo)1-3(C1-8)alkoxy, hydroxy and hydroxy(C1-8)alkyl; and, wherein any of the foregoing heterocyclyl substituents are optionally substituted with oxo)), cycloalkyl (wherein cycloalkyl is optionally substituted with one to four substituents independently selected from the group consisting of C1-8alkyl, C1-8alkoxy, C1-8alkoxy(C1-8))alkyl, carboxyl, carboxyl(C1-8)alkyl, amino (substituted with a substituent independently selected from the group consisting of hydrogen and C1-4alkyl), amino(C1-8)alkyl (wherein amino is substituted with a substituent independently selected from the group consisting of hydrogen and C1-4alkyl), halogen, (halo)1-3(C1-8)alkyl, (halo)1-3(C1-8)alkoxy, hydroxy and hydroxy(C1-8)alkyl), xe2x80x94(Oxe2x80x94(CH2)1-6)1-5xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94(CH2)1-6xe2x80x94Oxe2x80x94(CH2)1-6xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94(CH2)1-6xe2x80x94Oxe2x80x94(CH2)1-6xe2x80x94Oxe2x80x94(CH2)1-6xe2x80x94Oxe2x80x94, xe2x80x94(Oxe2x80x94(CH2)1-6)1-5xe2x80x94NR6xe2x80x94, xe2x80x94Oxe2x80x94(CH2)1-6xe2x80x94NR6xe2x80x94(CH2)1-6xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94(CH2)1-6xe2x80x94Oxe2x80x94(CH2)1-6)0-5xe2x80x94Sxe2x80x94, xe2x80x94Oxe2x80x94(CH2)1-6xe2x80x94Sxe2x80x94(CH2)1-6xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94(CH2)1-6xe2x80x94Oxe2x80x94(CH2)1-6xe2x80x94Sxe2x80x94, xe2x80x94NR6xe2x80x94NR7xe2x80x94, xe2x80x94NR6xe2x80x94(CH2)1-6xe2x80x94NR7xe2x80x94, xe2x80x94NR6xe2x80x94(CH2)1-6xe2x80x94NR7xe2x80x94(CH2)1-6xe2x80x94NR8xe2x80x94, xe2x80x94NR9xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94NR9xe2x80x94, xe2x80x94C(O)xe2x80x94(CH2)0-6xe2x80x94NR6xe2x80x94(CH2)0-6xe2x80x94C(O)xe2x80x94, xe2x80x94NR6xe2x80x94(CH2)0-6xe2x80x94C(O)xe2x80x94(CH2)1-6xe2x80x94C(O)xe2x80x94(CH2)0-6xe2x80x94NR7xe2x80x94, xe2x80x94NR6xe2x80x94C(O)xe2x80x94NR7xe2x80x94, xe2x80x94NR6xe2x80x94C(NR7)xe2x80x94NR8xe2x80x94, xe2x80x94Oxe2x80x94(CH2)1-6xe2x80x94NR6xe2x80x94(CH2)1-6xe2x80x94Sxe2x80x94, xe2x80x94Sxe2x80x94(CH2)1-6xe2x80x94NR6xe2x80x94(CH2)1-6xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94(CH2)1-6xe2x80x94NR6xe2x80x94(CH2)1-6xe2x80x94Sxe2x80x94 and xe2x80x94NR6xe2x80x94(CH2)1-6xe2x80x94Sxe2x80x94(CH2)1-6xe2x80x94NR7xe2x80x94 (wherein R6, R7 and R8 are independently selected from the group consisting of hydrogen, C1-8alkyl, C1-8alkoxy(C1-8)alkyl, carboxyl(C1-8)alkyl, amino(C1-8)alkyl (wherein amino is substituted with a substituent independently selected from the group consisting of hydrogen and C1-4alkyl), hydroxy(C1-8)alkyl, heterocyclyl(C1-8)alkyl, aryl(C1-8)alkyl and heteroaryl(C1-8)alkyl (wherein the foregoing heterocyclyl, aryl and heteroaryl substituents are optionally substituted with one to four substituents independently selected from the group consisting of C1-8alkyl, C1-8alkoxy, C1-8alkoxy(C1-8)alkyl, carboxyl, carboxyl(C1-8)alkyl, amino (substituted with a substituent independently selected from the group consisting of hydrogen and C1-4alkyl), amino(C1-8)alkyl (wherein amino is substituted with a substituent independently selected from the group consisting of hydrogen and C1-4alkyl), halogen, (halo)1-3(C1-8)alkyl, (halo)1-3(C1-8)alkoxy, hydroxy and hydroxy(C1-8)alkyl; and, wherein heterocyclyl is optionally substituted with oxo); and, wherein R8 is selected from the group consisting of C1-8alkyl, C1-8alkoxy(C1-8)alkyl, carboxyl(C1-8)alkyl, amino(C1-8)alkyl (wherein amino is substituted with a substituent independently selected from the group consisting of hydrogen and C1-4alkyl), hydroxy(C1-8)alkyl, heterocyclyl(C1-8)alkyl, aryl(C1-8)alkyl and heteroaryl(C1-8)alkyl (wherein the foregoing heterocyclyl, aryl and heteroaryl substituents are optionally substituted with one to four substituents independently selected from the group consisting of C1-8alkyl, C1-8alkoxy, C1-8alkoxy(C1-8)alkyl, carboxyl, carboxyl(C1-8)alkyl, amino (substituted with a substituent independently selected from the group consisting of hydrogen and C1-4alkyl), amino(C1-8)alkyl (wherein amino is substituted with a substituent independently selected from the group consisting of hydrogen and C1-4alkyl), halogen, (halo)1-3(C1-8)alkyl, (halo)1-3(C1-8)alkoxy, hydroxy and hydroxy(C1-8)alkyl; and, wherein heterocyclyl is optionally substituted with oxo)); and,
R1 and R3 are independently selected from the group consisting of hydrogen, C1-8alkyl, C2-8alkenyl, C2-8alkynyl (wherein alkyl, alkenyl and alkynyl are optionally substituted with a substituent selected from the group consisting of C1-8alkoxy, alkoxy(C1-8)alkyl, carboxyl, carboxyl(C1-8)alkyl, amino (substituted with a substituent independently selected from the group consisting of hydrogen and C1-4alkyl), amino(C1-8)alkyl (wherein amino is substituted with a substituent independently selected from the group consisting of hydrogen and C1-4alkyl), (halo)1-3, (halo)1-3(C1-8)alkyl, (halo)1-3(C1-8)alkoxy, hydroxy, hydroxy(C1-8)alkyl and oxo), C1-8alkoxy, C1-8alkoxycarbonyl, (halo)1-3(C1-8)alkoxy, C1-8alkylthio, aryl, heteroaryl (wherein aryl and heteroaryl are optionally substituted with a substituent selected from the group consisting of C1-8alkyl, C1-8alkoxy, alkoxy(C1-8)alkyl, carboxyl, carboxyl(C1-8)alkyl, amino (substituted with a substituent independently selected from the group consisting of hydrogen and C1-4alkyl), amino(C1-8)alkyl (wherein amino is substituted with a substituent independently selected from the group consisting of hydrogen and C1-4alkyl), halogen, (halo)1-3(C1-8)alkyl, (halo)1-3(C1-8)alkoxy, hydroxy and hydroxy(C1-8)alkyl), amino (substituted with a substituent independently selected from the group consisting of hydrogen and C1-4alkyl), cyano, halogen, hydroxy and nitro;
and pharmaceutically acceptable salts thereof.
The present invention is directed to macroheterocyclic compounds useful as a selective kinase or dual-kinase inhibitor; preferably as inhibitors of kinases selected from protein kinase C or glycogen synthase kinase-3; and, more particularly, a kinase selected from protein kinase C xcex1, protein kinase C xcex2-II, protein kinase C xcex3 or glycogen synthase kinase-3xcex2.
The present invention is also directed to methods for producing the instant macroheterocyclic compounds and pharmaceutical compositions and medicaments thereof.
The present invention is further directed to methods for treating or ameliorating a kinase or dual-kinase mediated disorder. In particular, the method of the present invention is directed to treating or ameliorating a kinase mediated disorder such as, but not limited to, cardiovascular diseases, diabetes, diabetes-associated disorders, inflammatory diseases, immunological disorders, dermatological disorders, oncological disorders and CNS (Central Nervous System) disorders.